This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Heavy metals, pesticides, and other environmental factors have been shown to have a profound effect on the complex Ca2+ signaling mechanism of the cell. We found evidence, that synchronized random variation (correlated environmental noise) on the operation of the calcium channels and on the binding process of an agonist to the G-protein coupled receptor (GPCR) have an impact on the Ca2+ dynamics through a mechanism known as stochastic resonance (SR). The calcium channels and the GPCR impacted by noise from different sources or with different spatial and temporal properties will be studied. The effect of internal noise (arising from the highly inhomogeneous nature of the cell) on concentrations and on the operation of the IP3 receptor (IP3R) will be also considered. We continue to develop the ComBRe model, which is based on a GPCR-based model and a Ca2+-induced Ca2+-release (CICR) based model, and we will consider a biphasic regulation of IP3R that accounts for the interaction among the activating and inhibiting calcium and the IP3 binding site. Experiments will be designed with the necessary student training to collect experimental data (cytosolic calcium vs. time traces) in response to various environmental factors, such as K+ ions and dopamine, to modify and ultimately validate the model. The goal of the project is to establish a numerical model which is validated by experimental results, sensitive to environmental noise, and can serve as a viable tool to gain better understanding of calcium dynamics and being able to predict physiological effects of various environmental factors.